For many patients, highly active antiretroviral therapy (HAART) reduces human immunodeficiency virus (HIV) plasma viral load to undetectable levels. Viral proliferation is not completely suppressed, however, as evidenced by low level de novo cell infection. With the withdrawal of therapy, viremia returns. One reason for this is the presence of virions in anatomical compartments that partially exclude the penetration of one or more of the HAART drugs, i.e., drug sanctuaries that act as viral reservoirs. Another reason can be ongoing viral replication due to imperfect adherence to the drug-taking regimen. Patients not fully adherent are more likely to have subtherapeutic drug levels. The 2-LTR HTV episomal DNA fraction represents an ephemeral form of the virus that has recently infected cells. It can be quantified and sequenced along with adjoining genes using primers that cross the 2-LTR ligation site. We propose to sequence the polymerase gene from the 2-LTR episornal forms of HIV from the blood and semen from patients whose adherence is being followed by the use of MEMS caps electronic monitors and by the concentration of the antiretrovirals in these fluids. This will elucidate the residually replicating form of HTV present in the blood and semen, allowing us to contrast the relative permeability of antiretroviral compounds in the seminal compartment to the resistant viral forms present. By following these forms over a period of time, the seminal compartment can be evaluated as a drug sanctuary and its role in reemergent viremia can be assessed. It is our hypothesis that, in the presence of adherence to an antiretroviral regimen, the residually replicating HIV forms that are found in seminal fluids will be the more fit drug sensitive virus genotype for the drugs that poorly penetrate the blood-semen barrier. These will contrast to the concurrent forms of virus in the blood which will be resistant. In the absence of adherence, sensitive viral forms will be found in both plasma and seminal fluid. In cases of emergent viremia, the viral forms in the blood will phylogenetically cluster with the residually replicating forms in the seminal compartment, and the semen will be a representative viral sanctuary and reservoir. This will elucidate the virus population dynamics and resistance acquisition in a representative viral reservoir.